You are on page 1of 5

Clinical Efficacy of Topical Clindamycin Phosphate

and Azelaic Acid on Acne Vulgaris and Emergence


of Resistant Coagulase-Negative Staphylococci
Turk J Med Sci
30 (2000) 483-487
@ TBTAK
483
Abstract: In this study, the uses of topical
clindamycin phosphate and azelaic acid were
compared from point of clinical efficacy and
emergence of resistant coagulase-negative
staphylococci (CNS). Each group contained
20 patients. Pre- and post-treatment acne
grades and comparison of two groups were
evaluated by using the Wilcoxon and
Spearman statistical techniques. The
sensitivity of CNS to azelaic acid and to
clindamycin phosphate were searched by
microbroth dilution technique. Azelaic acid
was found more effective in reducing acne
grade. Eleven CNS strains were found
resistant to clindamycin phosphate before
treatment. After 8 weeks of therapy with
topical clindamycin phosphate 18 of 20 CNS
strains were resistant to this agent. No
difference was detected for the MIC (minimal
inhibitory concentration) values of CNS
before and after topical azelaic acid
treatment.
Key Words: Acne vulgaris treatment,
clindamycin phosphate, azelaic acid.
Metin ZKAN
1
Gl DURMAZ
2
lham SABUNCU
1
Nurhan SARAOLU
1
Yurdanur AKGN
2
Selim Murat RER
1
Received: March, 17, 1997
Divisions of
1
Dermatology and
2
Microbiology,
Faculty of Medicine, Osmangazi University,
Eskiehir-Turkey
Introduction
Acne vulgaris is the most common skin disease taking
its origin from the pilosebaceous follicles. It affects nearly
80% of young adults, aged 11 to 30 years. It may cause
disfiguration and permanent scarring and also it may have
an adverse effect on psychological development, resulting
in profound emotional scarring which may lead to social
phobias, withdrawal from society, and clinical depression
(1, 2, 3). The four main pathogenic factors in the
development of acne are increased sebum production,
disorders of the microbial flora, cornification of the
pilosebaceous duct, and inflammation (1). For an
effective treatment the drugs should be capable of
influencing one or more of these factors in the
pathogenesis of acne vulgaris.
The patients who have non-inflammatory comedones
or mild to moderate acne are usually treated by topical
agents. Azelaic acid and clindamycin phosphate are two of
these drugs. The first one is a naturally occurring
saturated C
9
dicarboxylic acid and a relatively new drug.
The second agent is one of the most commonly used
topical antibiotics in acne treatment (4, 5, 6).
Because of the widespread use of antibiotics in the
treatment of acne, there has been increasing concern
regarding the emergence of bacterial antibiotic resistance
in the resident flora of the skin and gastrointestinal tract.
Systemic antibiotic therapy has been shown to be
associated with an increase in multiple resistant CNS. This
has potentially serious consequences for patients and
their contacts. CNS have been found to be pathogenic in
patients with indwelling catheters, in surgical patients,
and in neonates. In addition, the ability of CNS to transfer
resistance via plasmids to the more pathogenic S. aureus
has been demonstrated. Information is scanty regarding
the development of resistant staphylococci during
treatment with topical antibiotics (7).
In this study we investigated the emergence of
resistant CNS after 8 weeks of topical therapy with
azelaic acid and clindamycin phosphate, and we compared
their clinical efficacy.
Materials and Methods
1. Patients
This study was designed as a randomized and
controlled trial. Patients were selected from the ones
coming to The Hospital of Medical Faculty of Osmangazi
University. The eligibility criteria for this study were
being older than 18 or having the permission of the
parents, having an acne grade less than or equal to 3.0
according to the Leeds acne assessment technique (4).
This technique has been reported to be a quick and
Clinical Efficacy of Topical Clindamycin Phosphate and Azelaic Acid on Acne Vulgaris and Emergence of Resistant Coagulase-Negative Staphylococci
satisfactory method for clinical studies related with acne
vulgaris. Pregnant or nursing women, the ones who had
been using any acne treatment during the last month, the
female patients who had taken estrogen preparations in
the last three months were excluded from this study.
At the beginning of the study, each patient was
informed about the treatment period and the possible
adverse effects and written or oral consent was taken
from the patient or his/her parents. The study was also
permitted by the ethics committee of The Medical Faculty.
The patients were applied either topical azelaic acid or
topical clindamycin phosphate therapy until 20 patients
for each group completed the study. The acne grade of
each patient was noted at the beginning of the study
according to the Leeds technique (4). For this purpose,
the patients were examined by inspection and palpation in
a well-illuminated room. The patients whose acne grades
were higher than 3.0 were not included in the study.
The differences between the ages, sexes, and the acne
grades at the beginning of therapy in both patients
groups were not statistically significant (Table 1-2)
(Mann-Whitney-U Test, U=175.5; p>0.05).
At the end of therapy, the acne grades of the patients
were assessed using the Leeds technique. For both
groups, the differences between the pre- and post-
treatment acne grades and comparison of two groups
were evaluated by using the Wilcoxon and Spearman
statistical techniques.
2. Microbiological examination
The aforementioned drugs were applied to the
patients twice daily for 8 weeks. Samples for
bacteriological cultures were taken from the hairline,
forehead and glabella at the beginning and at the end of
8 weeks. These samples were inoculated in the blood
agar. After an overnight incubation at 35C, the colonies
which performed appropriate properties as morphology,
Gram staining, and coagulase reactions were determined
as CNS. The sensitivity of these CNS to azelaic acid and
clindamycin phosphate were searched by microbroth
dilution technique (9, 10). The 24 hours cultures of the
CNS were adjusted to 0.5 Mc Farland turbidity (5x10
8
CFU/ml). Then these suspensions were diluted to 1:10
with distilled water. Ninety-four grams of azelaic acid was
dissolved in 10 mol/L NaOH and 0.1 mol/L phosphate
buffer and a stock solution was prepared in which had
0.5 mol/L azelaic acid in. Also 128 g/ml clindamycin
phosphate main solution was prepared. These stock
484
Acne grade MIC (mol/L)
Patient Age Sex Pretreatment Posttreatment Pretreatment Posttreatment
number
1 27 F 1.5 0.5 0.007 0.007
2 23 M 2.0 0.75 0.007 0.007
3 23 F 2.5 1.5 0.015 0.015
4 17 F 2.0 1.25 0.007 0.007
5 19 M 2.0 1.5 0.03 0.03
6 22 F 1.25 0.5 0.03 0.015
7 23 F 1.25 1.0 0.03 0.03
8 25 F 2.0 0.5 0.03 0.03
9 18 F 2.0 1.5 0.015 0.015
10 20 F 1.25 0.5 0.015 0.015
11 18 F 2.0 2.0 0.007 0.007
12 24 F 1.25 0.5 0.007 0.007
13 21 F 3.0 1.5 0.015 0.015
14 21 F 1.0 1.0 0.007 0.007
15 20 M 1.25 1.0 0.015 0.015
16 23 F 1.0 0.5 0.003 0.007
17 21 F 2.5 1.0 0.007 0.007
18 18 F 2.5 1.5 0.03 0.03
19 20 M 1.5 0.5 0.03 0.03
20 14 M 1.5 1.0 0.015 0.015
Table 1. The result of patients who were treated with azeleic acid concerning age, sex and acne grade.
M. ZKAN, G. DURMAZ et al.
solutions were diluted by two folds in Mueller Hinton
Broth (dilution range: 0.5 to 0.003 mol/L, 128 to 0.12
g/ml, respectively).
Microplates were incubated for 16 to 20 hours at
35C. For the clindamycin phosphate group the MIC
values equal to or more than 4g/ml were accepted as
resistant (10, 11).
Results
1. Clinical
The responses of the patients to the treatmet were
measured by the decrease of the acne grade of each
patient. The clinical improvement for both groups was
found to be significant (Table 1 and 2) (T=0, p<0.01).
When the clinical improvement rates of the two
groups were compared with each other, the clinical
improvement in the azelaic acid group was found to be
more significant than the clindamycin phosphate group.
Especially for the clindamycin group, side effects like
erythema, burning, dryness, and peeling were noted in
rare instances at the early days of therapy. These side
effects were not the cause of cessation of therapy and
almost entirely disappeared on the following days.
2. Microbiological
In the examination of the coagulase negative
staphylococci isolated from the patients at the beginning
of the study and at the end of 8 weeks, the following
result were obtained:
a) In the azelaic acid group, the MIC values of the CNS
were not observed to be significantly different beforeand
after treatment (Table 1).
b) In the clindamycin phosphate group 11 CNS
isolates were resistant to this drug before treatment.
After 8 weeks of therapy with topical clindamycin
phosphate, 18 of 20 CNS isolates were resistant to this
drug. Eight of 20 CNS isolates presented no difference of
MIC values before and after treatment. The other 12
strains, however, presented 2 to 8 times higher MIC
values after therapy when compared with the MIC values
before therapy (Table 2).
c) The species of CNS which were sensitive to
clindamycin phosphate before treatment had higher MIC
values after treatment.
Discussion
Acne vulgaris is one of the most common diseases
seen in the dermatology clinics. Although it is not a life-
485
Acne grade MIC (g/mL)
Patient number Age Sex Pretreatment Posttreatment Pretreatment Posttreatment
1 27 F 1.5 1.0 8 8
2 21 F 2.0 1.5 4 4
3 18 F 1.25 1.0 0.5 4
4 26 F 2.0 1.5 2 4
5 19 M 2.5 2.0 8 16
6 21 F 1.0 1.0 4 8
7 25 F 3.0 2.5 0.5 4
8 21 M 1.25 1.0 4 8
9 20 F 2.5 2.0 0.5 4
10 21 F 1.25 1.25 0.5 0.5
11 23 M 2.0 1.5 0.5 4
12 19 F 1.5 0.75 4 8
13 21 M 1.0 1.0 8 8
14 18 F 1.5 1.0 8 8
15 25 F 1.25 1.25 0.5 4
16 22 M 2.0 2.0 0.5 4
17 24 F 1.0 0.5 4 4
18 19 F 2.0 1.5 16 32
19 22 M 1.5 0.5 4 4
20 23 F 1.0 0.75 2 2
Table 2. The result of patients who were treated with clindamycin phosphate concerning age, sex and acne grade.
Clinical Efficacy of Topical Clindamycin Phosphate and Azelaic Acid on Acne Vulgaris and Emergence of Resistant Coagulase-Negative Staphylococci
threatening disease it can seriously affect the quality of
life (12, 13). During the last 20 years new data about the
pathogenesis of acne has been recognized and by this
mean a number of new drugs have entered to acne
therapy. These drugs usually affect one or more of the
four aforementioned pathogenic factors of acne (14, 15).
Antibiotics are commonly used in acne therapy. They
are used topically or systemically. Tetracyline,
clindamycin, and erythromycin are the mostly used
antibiotics. These drugs also have anti-inflammatory
effects besides their antimicrobial effects (4, 15). Azelaic
acid is a naturally occurring dicarboxylic acid and a
relatively new drug in acne therapy. It is reported that
azelaic acid has a strong effect on microbial flora and a
moderate effect on inflammation; thus it affects 2 of the
4 main factors in the pathogenesis (4).
In this study we planned to compare the efficacy of
topical clindamycin phosphate and topical azelaic acid
both clinically and microbiologically in acne therapy. Since
both azelaic acid and clindamycin phosphate have
antimicrobial effects, development of bacterial resistance
is directly related with the therapeutic efficacy of these
drugs. There are any studies which suggest that there is
a significant development of resistance during the use of
topical clindamycin but no reports have been yet written
on this matter for azelaic acid (15, 16, 17). At the end of
the study we found that both drugs were effective in the
treatment of acne vulgaris, but azelaic acid was
considered to be more effective in reducing acne grade.
The clindamycin resistance of the CNS showed an increase
during the 8 weeks therapy with this drug whereas there
was no difference in the azelaic acid resistance in the
other group.
The better clinical results in the azelaic acid group may
be due to no development of resistance to this drug and
also the number of the affected pathogenic ways by these
two drugs may be another factor. Clindamycin has only
antibacterial and anti-inflammatory effects whereas
azelaic acid has also an effect on follicular keratinization
(4).
On the other hand CNS are the members of the
normal skin flora and are the most common
staphyloccocci species isolated from cutaneous sites.
These microorganisms are easily shed from skin and may
contaminate inanimate environmental surfaces, other
people, and the air. CNS infections in surgical sites usual
result from contamination by these organisms originating
from the patients skin or nasopharynx or coming from
exogenous sources. Therefore colonization of resistant
CNS strains may cause some problems in treatment of
severe CNS infections (18).
Correspondence author:
Gl DURMAZ
Vineli Mah. Takpr Cad. Deniz Apt. 27/13
26020 Eskiehir-TURKEY
1. Ebling FJG, Cunliffe WJ. Disorders of
the sebaceous glands. Textbook of
Dermatology, Fifth Edition (Ed:
Champion RH, Burton JL, Ebling FJG),
Blackwell Scientific Publications,
1993, pp: 1699-1744.
2. Savakan H, Acar MA, Memiolu HR.
Ya bezi hastalklar. Dermatoloji, 2.
Bask (Ed: Tzn Y, Kotoyan A,
Aydemir EH, Barans O), stanbul,
Nobel Tp Ktabevi, 1994, sh: 483-
494.
3. Strauss JS. Sebaceous glands: Acne
vulgaris, Dermatology in General
Medicine, 4th Edition (Ed: Fitzpatrick
TB Eizen AZ, Wolff K), McGraw-Hills
Inc., 1993, pp: 709-726.
4. Gollnick H. New therapeutic agent:
azelaic acid in acne treatment. J
Dermatol Treat 1: 23, 1990.
5. Kayaalp O: Tbbi Farmakoloji, 1. Cilt, 5.
Bask. Ankara, Feryal Matbaaclk,
1989, sh: 685-688.
6. Nazzaro Porro M, Passi S, Picardo M.
Beneficial effects of 15% azelaic acid
cream on acne vulgaris. Br J Dermatol
109: 45, 1983.
7. Harkaway KS, McGinley KJ, Foglia AN,
Antibiotic resistance patterns in
coagulase negative staphylococci after
treatment with topical erythromycin,
benzoyl peroxide, and combination
therapy. Br J Dermatol 126: 586,
1992.
8. Burke BM, Cunliffe WJ. The
assessment of acne vulgaris- the Leeds
technique. Br J Dermatol 111: 83,
1984.
9. Baron EJ, Peterson LR, Finegold SM:
Bailey & Scotts Diagnostic
Microbiology, 9th Edition. The C.V.
Mosby Compan, 1994, p: 321.
10. Stokes EJ, Ridgway GL, Wren MWD:
Clinical Microbiology, 7th Edition.
Edward Arnold, A Division of Hadder &
Stoughton, London, 1993, p: 259.
11. Jones RN, Barry AL, Goven JL,
Washinton JA. Suspectibility tests:
macrodilution and microdilution broth
procedures. Manual of Clinical
Microbiology, 4th Edition (Ed: Lennette
EH, Balows A, Hausler WJ, Shadomy
HJ), American Society for
Microbiology, 1985, p: 972.
486
References
M. ZKAN, G. DURMAZ et al.
12. Bergfeld WF. The evaluation and
management of acne: Economic
considerations. J Am Acad Dermatol
32: 52, 1995.
13. Koo J. The psychosocial impact of
acne: Patients perceptions. J Am Acad
Dermatol 32: 26, 1995.
14. Eady EA, Holland KT, Cunliffe WJ.
Should topical antibiotics be used for
the treatment of acne vulgaris. Br J
Dermatol 7: 50, 1982.
15. Gratton D, Raymond GP. Topical
clindamycin versus systemic
tetracycline in the treatment of acne. J
Am Acad Dermatol 7: 50, 1982.
16. Brown JM, Poston JM. Resistance of
propionibacteria to antibiotics used in
the treatment of acne vulgaris. J Med
Microbiol 16: 271, 1983.
17. Eady EA, Cove JH. Erythromycin
resistant propionibacteria in antibiotic
treated patients. Br J Dermatol 121:
51, 1989.
18. Ruben FL, Norden CW. Staphylococcal
infections. Bacterial Infections of
Humans, Epidemiology and Control,
Second Edition (Ed: EvansAS,
Brachman PS), Plenum Medical
Company, New York and London,
1991, pp: 621-637.
487